2015 Center for Medical Counter Measures Against Radiation (CMCR) Overview

The University of Pittsburgh, Center for Medical Counter Measures Against Radiation began its 11th year on September 1, 2015. There are multiple changes and revisions to the operations of the Pitt CMCR, and also the CMCR Program.

Please consult web section: Center Coordinating Core (CCC), Joel S. Greenberger, M.D., Principal Investigator, and please note the section on application for pilot projects and drug development funding opportunities in the announcement for the Opportunities Fund Management Core (OFMC), Sally Amundson, Ph.D., Principal Investigator (Columbia University CMCR).

The CMCR program was created in 2005 to increase collaborative efforts between academic institutions working to develop new medical technology for defense of the public. Growing terrorist threats have highlighted gaps in research and development of medical countermeasures for protection of the US civilian population against radiation. Few products are currently available for mitigation of radiation injury, for treatment of post-exposure injury, or for the rapid identification of exposed individuals requiring treatment.

There are four projects in the Pitt CMCR (Fig 1) managed by four principal investigators: Joel S. Greenberger, M.D., Valerian Kagan, Ph.D., Hulya Bayir, M.D., and Jian Yu, Ph.D. These four projects are supported by six scientific cores of operations including innovative chemistry (Drs. P. Wipf and D. Stoyanovsky), lipidomics (Dr. Y. Tyurina), computational pharmacology modeling of the interaction of different radiation mitigators (Dr. I. Bahar), Radiobiology (Dr. M. Epperly), imaging radiation pathology (Dr. S. Watkins), and statistical evaluations (Dr. H. Wang). The Pitt CMCR continues its focus on research topics related to the past 10 years of investigations on “mitochondrial mechanisms of radiation mitigation”; however, research efforts have expanded into multiple mechanisms of irradiation damage and repair, and the identification and development of new molecular targets for design and discovery of new radiation mitigators (Fig 2).

The overarching goal of the Pitt CMCR is to explore and identify the new pathways through which lipid mediators are involved in the progression of radiation disease. This will be achieved by the employment of contemporary lipidomics and redox lipidomics. New areas include research on: lipid mediator/cytokine regulation of inflammatory responses and immune cells (particularly, neutrophils) in their interactions with intestinal microbiota activated by disrupted intestinal epithelial barrier (Project 2, Valerian Kagan, Ph.D., Principal Investigator) and triggering programmed cell death mechanisms, including necroptosis and ferroptosis (Project 3, Hulya Bayir, M.D., Principal Investigator). Additionally, there is a new focus on the role of the intestinal stem cells and differentiated intestinal crypt cells in maintaining and restoring intestinal integrity after total body irradiation (Project 4, Jian Yu, Ph.D., Principal Investigator). Overall idea of multi-stage therapy of “radiation disease” by optimized combinations/cocktails of multi-targeted drugs will be explored by Project 1 (Joel S. Greenberger, M.D., Principal Investigator).

The discovery of new radiation mitigators has focused on the interaction of the irradiation damaged intestine with gut bacteria, which if unchecked and un-mitigated can lead to systemic infection, sepsis, and death. Novel 3-dimensional intestinal crypt culture systems (Project 4, Jian Yu, Ph.D.) will be utilized to correlate with in vivo studies in mice to identify the cellular targets for action of new phospholipase inhibitor drugs, which we hypothesize can minimize damage from the migration into crypts of neutrophils. Neutrophils, which are recruited to combat bacterial infection, can cause structural damage in the intestine, which can lead to further damage to tissue structure (Project 2, Valerian Kagan, Ph.D., Principal Investigator) (4).

Mission and Focus of the Pitt CMCR

Building upon research carried out over the past 10 years, several lead small molecule compound drugs are being translated from the drug discovery phase into the drug development phase. Three lead compounds include:

  1. GS-nitroxides, JP4-039 and XJB-5-131 (1)
  2. Water-soluble – DMSO analog, MMS350 (2)
  3. Imidazole-Fatty Acids (6)

New potential small molecule radiation mitigators have been shown to be effective in increasing survival in total body irradiated mice when delivered 24 hrs. or later after irradiation include: Necrostatin-1, Varespladib (Fig. 2) (3), Mito-Ebselen, Imidizole-Fatty Acids (6), and R-Bel (3).

Pilot Project Collaborations with the Pitt CMCR

In coordination with the Opportunities Fund Management Core (OFMC), Sally Amundson, Ph.D., Principal Investigator, Columbia CMCR, the Pitt CMCR welcomes opportunities for collaboration with scientists and investigators interested in the development of small molecule radiation mitigators. In particular, elucidation of the mechanism of action of those small molecule radiation mitigators described above, and discovery of new mitigators will be the focus of collaborative research. The availability of specific transgenic, conditional knockout, conditional knock-in, and other model systems for validating and explaining the mechanisms of action of Pitt CMCR drugs will be a priority for collaborative interactions.

Specific Projects of Interest

The Pitt CMCR investigators are working with several model systems already to expand and document the effectiveness and safety of the Pitt CMCR drugs. These model systems include:

  1. Experiments with pregnant female mice elucidating toxicities and effectiveness of mitigation in fetal mice (9).
  2. Studies with Fanconi Anemia (Fancd2-/-) radiosensitive mice, as a model system for the “radiosensitive” human population that will be particularly susceptible to toxicity and lethality of total body irradiation (7).
  3. Studies with SAMP6 mice as a model system for senescence associated (age-associated) osteoporosis and other skeletal defects, and combined injury (skeletal fracture with irradiation, infection with irradiation, traumatic brain injury with irradiation, thermal injury with irradiation, and tissue wounding and irradiation). These mice are a model system for the elderly (8).
  4. Studies comparing the effectiveness of CMCR drugs on total body irradiated female compared to male mice.
  5. Studies with 3D intestinal crypt culture to understand the actions of CMCR drugs in crypt injury and recovery after radiation.


  1. Rwigema Jean-Claude M, Beck Barbara, Wang Wei, Doemling Alexander, Epperly Michael W, Shields Donna, Franicola Darcy, Dixon Tracy, Frantz Marie-Celine, Wipf Peter, Tyurina Yulia, Kagan Valerian E, Wang Hong, and Greenberger Joel S. Two strategies for the development of mitochondrial-targeted small molecule radiation damage mitigators. Int J Radiat Oncol Biol Phys, 80(3): 860-868, 2011.
  2. Kalash Ronny, Epperly Michael W, Goff Julie, Dixon Tracy, Sprachman Melissa M, Zhang Xichen, Shields Donna, Cao Shaonan, Wipf Peter, Franicola Darcy, Berhane Hebist, and Greenberger Joel S. Amelioration of irradiation pulmonary fibrosis by a water-soluble bifunctional sulfoxide radiation mitigator (MMS350). Radiat Res, 180: 474-490, 2013.
  3. Tyurina Yulia Y, Poloyac Samuel M, Tyurin Vladimir A, Kapralov Alexander A, Jiang Jianfei, Anthonymuthus Tamil Selvan, Kapralova Valentina I, Vikulina Anna S, Jung Mi-Jeon, Epperly Michael W, Mohammadyani Dariush, Klein-Seetharaman Judith, Jackson Travis C, Rochanek Patrick M, Pitt Bruce R, Greenberger Joel S, Vladimirov Yury A, Bayir Hulya, and Kagan Valerian E. A mitochondrial pathway for biosynthesis of lipid mediators. Nature Chemistry, On-Line: xx: 1-12, 2014.
  4. Leibowitz Brian J, Wei Liang, Zhang Lin, Ping Xiaochun, Epperly Michael, Greenberger Joel, Cheng Tao, and Yu Jian. Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice. Nature Communications, 5: 3494, 2014.
  5. Greenberger Joel S, Berhane Hebist, Shinde Ashwin, Rhieu Byung Han, Bernard Mark, Wipf Peter, Skoda Erin M, and Epperly Michael W. Can radiosensitivity associated with defects in DNA repair be overcome by mitochondrial-targeted antioxidant radioprotectors? Frontiers in Radiation Oncology, 41: 1: (PMC3926189), 2014.
  6. Atkinson Jeffrey, Kapralov Alexandr A, Yanamala Naveena, Pearce Linda, Peterson Jim, Tyurina Yulia Y, Epperly Michael W, Huang Zhentai, Jiang Jianfei, Maeda Akihiro, Feng Weihong, Wasserloos Karla, Belikova Natalia A, Tyurin Vladimir A, Fletcher Jackie, Wang Yongsheng, Vlasova Irina I, Klein-Seetharaman Judith, Stoyanovsky Detcho A, Bayir Hulya, Pitt Bruce R, Greenberger Joel S, and Kagan Valerian E. A mitochondria-targeted inhibitor of cytochrome C peroxidase mitigates radiation induced death. Nature Communications, 2: 497, 2011.
  7. Berhane Hebist, Epperly Michael W, Goff Julie, Kalash Ronny, Cao Shaonan, Franicola Darcy, Zhang Xichen, Shields Donna, Houghton Frank, Wang Hong, Sprachman Melissa, Wipf Peter, Li Song, Gao Xiang, Parmar Kalindi, and Greenberger Joel S. Radiobiologic differences between bone marrow stromal and hematopoietic progenitor cell lines from Fanconi Anemia (Fancd2-/-) mice. Radiat Res, 181: 76-89, 2014.
  8. Glowacki Julie, Mizuno Shuichi, Kung Jason, Goff Julie, Epperly Michael, Dixon Tracy, Wang Hong, and Greenberger Joel S. Effects of mouse genotype on bone wound healing and irradiation-induced delay. In Vivo, 28: 189-196, 2014.
  9. Kanter David, O'Brien Matthew B, Shi Xiao-Hua, Chu Tianjiao, Mishima Takuya, Beriwal Sushil, Epperly Michael W, Wipf Peter, Greenberger Joel S, and Sadovsky Yoel. The impact of ionizing radiation on placental trophoblasts. Placenta, PL13-10114, 1-7, 2014.
  10. Wang X, Wei L, Cramer J, Leibowitz B, Judge C, Epperly M, Greenberger J, Wang F, Li L, Stelzner M, Dunn J, Martin M, Lagasse E, Zhang L, and Yu J. Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation. Sci Rep, 5: 8566, 2015.